S137: IMPACT OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN FIRST COMPLETE REMISSION PLUS FLT3 INHIBITION WITH QUIZARTINIB IN ACUTE MYELOID LEUKEMIA WITH FLT3-ITD: RESULTS FROM QUANTUM-FIRST
Authors: Richard Schlenk, Pau Montesinos, Antonio Romero-Aguilar, Radovan Vrhovac, Elżbieta Patkowska, Hee-Je Kim, Pavel Zak, Po-Nan Wang, James Hanyok, LI Liu, Yasser Mostafa Kamel, Aziz Benzohra, Arnaud Lesegretain, Jorge Cortes, Mikkael A. Sekeres, Hervé Dombret, Sergio Amadori, Jianxiang Wang, Alexander E. Perl, Mark J. Levis, Harry P. Erba
Journal: HemaSphere (2023)

Background: Patients (pts) with acute myeloid leukemia (AML) and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)+ or FLT3 mutations face poor outcomes. The randomized, double-blind, placebo-controlled, phase 3 QuANTUM-First (NCT02668653) study evaluated the novel, highly potent, and selective type II FLT3 inhibitor quizartinib (Quiz) with standard chemotherapy in pts with FLT3-ITD+ newly diagnosed AML (ndAML). Quiz plus standard intensive induction, consolidation including allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1), followed by single-agent continuation therapy (Tx) for up to 3 years (y) significantly improved overall survival (OS). Aims: We evaluated 1) the impact of allo-HCT in CR1 and the interrelationship with Quiz on clinical results and 2) the association between FLT3-ITD minimal residual disease (MRD) pre‒allo-HCT and OS. Methods: Patients aged 18-75 y with ndAML were centrally screened for FLT3-ITD before starting standard induction Tx. Pts were randomized to Quiz (40 mg/d, on days 8-21) or placebo (PBO) and stratified by region (North/South America, Europe, and Asia/other regions), age (<60 y, ≥60 y), and white blood cell (WBC; <40×109/L, ≥40×109/L) at diagnosis. Pts achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 y of Quiz continuation Tx (30-60 mg/d) or PBO. The primary endpoint was OS. We assessed the impact of allo-HCT in CR1 on OS as a time-dependent covariable in multivariable regression analyses. P values were not adjusted for multiplicity. Results: In QuANTUM-First, 539 pts were randomized to Quiz (n=268) or PBO (n=271). The median age was 56 y (range, 20-75 y). There were 294 (54.5%) women and 245 (45.5%) men. Of the 539 randomized patients, 147 pts (54.9%) on Quiz and 150 (55.4%) on PBO achieved CR whereas 45 (16.8%) on Quiz and 26 (9.6%) on PBO achieved CRi after induction. Among pts who achieved CR (Quiz, n=147; PBO, n=150), 84 (57.1%) on Quiz and 73 (48.7%) on PBO underwent allo-HCT in CR1, predominantly with grafts from unrelated donors (49.7%), followed by siblings (32.5%) and other related donors (17.8%). The median time to allo-HCT in CR1 was 3.5 months in Quiz pts and 3.3 months in PBO pts. After completion of allo-HCT, 61 pts (72.6%) on Quiz and 36 (49.3%) on PBO started 3 y of continuation Tx. Another 115 allo-HCTs were performed outside CR1 (Quiz, n=60; PBO, n=55). A multivariable extended Cox regression was conducted in all randomized pts, stratified by region, age, and WBC, including allo-HCT in CR1 as time dependent and adjusted for FLT3-ITD variant allele frequency and sex. This analysis revealed Quiz treatment (hazard ratio [HR], 0.770; 95% CI, 0.609-0.973; P = 0.0284) and allo-HCT in CR1 (HR, 0.424; 95% CI, 0.301-0.597; P < 0.0001) as favorable factors to OS (Fig. 1). Simon-Makuch plot, used to analyze time-dependent effect of allo-HCT in CR1 on OS, showed that CR pts on Quiz had longer OS regardless of undergoing allo-HCT in CR1 or not (Fig. 2). Kaplan-Meier plot of OS in pts undergoing allo-HCT in CR1 by latest pre–allo-HCT FLT3-ITD MRD status (cutoff 10−4), showed longer OS with Quiz vs PBO particularly in pts with pre–allo-HCT MRD+ status (Fig. 3). Summary/Conclusion: Pts on Quiz had longer OS than pts on PBO, irrespective of allo-HCT in CR1. Pts on Quiz who underwent allo-HCT in CR1 had longer OS than pts on PBO, irrespective of pre–allo-HCT MRD status.Keywords: AML, flt3 inhibitor, Allogeneic hematopoietic stem cell transplant, Flt3-ITD